Novel Regenerative Therapeutic in Chronic Complex TBI Allopregnanolone (ALLO) is a neurosteroid endogenously produced in brain that exhibits pleiotropic actions highly relevant to the neurobiology and treatment of chronic complex TBI. ALLO exhibits pronounced regenerative actions, in addition to marked neuroprotective, analgesic, and anti-inflammatory effects in rodent models. Furthermore, our recent human data suggest that ALLO is decreased in TBI, suggesting that ameliorating deficits of this neurosteroid may be clinically therapeutic. We have also recently determined that ALLO levels are positively correlated with cortical gray matter thickness on MRI. In addition, multiple groups have now reported reductions in ALLO among patients with conditions that frequently co-occur with TBI, including depression and pain disorders. Replenishing ALLO could thus have tremendous therapeutic promise for multiple symptom constellations that greatly impact functional outcome and quality of life. The goal of this project is thus to conduct a proof-of-concept Phase 2 randomized controlled trial (RCT) in Veterans with chronic complex TBI to investigate the efficacy and tolerability of this regenerative therapeutic, providing critical foundational data in this population that could lead to a novel treatment addressing the multidimensional pathophysiological underpinnings of TBI and frequently co-occurring conditions such as depression and pain. This study will therefore provide initial data for the potential therapeutic efficacy of ALLO for co-occurring depression symptoms and pain symptoms (primary endpoints), as well as possible enhancement of functional outcome (secondary endpoint). In addition, we will examine TBI-only groups without depression or pain symptoms (also randomized to ALLO or placebo). This will now thus be a 4-arm study with 22 participants per group (88 total participants): Complex TBI groups (randomized to ALLO or placebo) and TBI-only groups (randomized to ALLO or placebo). As ALLO has anti-inflammatory actions, we will also investigate possible reductions in inflammatory biomarkers post-treatment (exploratory endpoint) and heart rate variability (exploratory endpoint). In addition, we will obtain important pharmacokinetic data for this intervention (ALLO levels to be quantified by mass spectrometry). Veterans with chronic complex TBI and a minimum HAM-D score of 14 (consistent with moderate depression) will be randomized to either intravenous placebo (6% cyclodextrin) or ALLO (0.5mg/ml of GMP-grade ALLO in 6% cyclodextrin); n=22 per group/n=44 with complex TBI. We will also randomize Veterans with TBI-only (no depression or pain symptoms) to ALLO or placebo; n=22 per group/n=44 with TBI-only. Total study number of OEF/OIF/OND Veteran participants with mild TBI will now be 88 (4 arms; 22 participants per group). Following a loading dose, Veterans will receive a 4-hour placebo or ALLO infusion targeted to achieve a serum ALLO level of 50 nanomolar (nM), which has been well-tolerated in small studies of other populations to date. Participants will receive intensive monitoring throughout the study, including continuous ECG. Blood will be drawn at hourly intervals during the infusion and 6 hours post-infusion to determine the pharmacokinetic parameters of ALLO in this cohort. As the potential antidepressant effect of ALLO may be very rapid, we will conduct behavioral assessments during the infusion, 6 hours post-infusion, and 24 hours post-infusion. In addition, we will examine these symptom constellations 7 days and 14 days post-infusion. We hypothesize that ALLO will be efficacious and well-tolerated in these chronic complex TBI and TBI-only populations, and that this intervention will have rapid antidepressant and analgesic actions (in addition to positive effects on functional outcome). We also hypothesize that inflammatory markers and improvements in heart rate variability may predict clinical response to this therapeutic candidate.